21-tri(lower alkyl)-siloxypregnane-3,20-diones



United States Patent 3,513,163 21-TRI(LOWER ALKYL)-SlLOXYPREGNANE-3,20- DIONES Edward A. Brown, Wilmette, Ill., assignor to G. D. Searle Co., Chicago, Ill., a corporation of Delaware No Drawing. Filed Feb. 12, 1968, Ser. No. 704,559 lint. Cl. C07c 173/00, 169/34 US. Cl. 26ti-23955 8 Claims ABSTRACT OF THE DISCLOSURE Preparation of the captioned compounds-for example, 171! hydroxy 21 trimethylsiloxypregn 4-ene-3,11,20- trioneand their valuable pharmacological properties including anti-inflammatory, neoglycogenetic, and occasional anti-algal activity-are disclosed.

The application for Letters Patent securing the invention herein described and claimed is a continuation-inpart of applicants prior copending application Ser. No. 528,410 filed Feb. 18, 1966, and now abandoned.

This invention relates to 21-tri(low alkyl)-siloxypregname-3,20-diones and congeners, and to processes for the preparation thereof. More particularly, this invention provides new, useful, and unobvious chemical compounds of the formula CHzOSlRa Typical of the lower alkyl radicals represented by R and R" are methyl, ethyl, propyl, isopropyl, butyl, secbutyl, tert-butyl, pentyl, neopentyl, hexyl, isohexyl, heptyl, and like monovalent, acrylic, unsaturated, straightor branched-chain, hydrocarbon groupings of empirical formula wherein n represents a positive integer less than 8. Those 3,513,163 Patented May 19, 1970 skilled in the art will recognize that a lower alkanoyloxy radical is a radical of the formula O-CO-lower alkyl the lower alkyl constituent being defined as before. Among the halogens represented by X and X, especially fluorine and chlorine are preferred.

The wavy line in the 16-position on the steroid nucleus signifies that the substituent represented by R" can be in either alpha or beta configuration except when R and R", taken together with carbon atoms 16 and 17 of the nucleus, give rise to a cyclic acetal, in which event alpha configuration obtains as indicated by the first formula in column 1.

The compounds to which this invention relates are useful by reason of their valuable pharmacological properties. Thus, for example, they share a capacity to counteract the edema and granuloma-formation characteristic of the inflammatory response to tissue insult. They are also neoglycogenetic and manifest occasional anti-algal activity. The product of Example 1 hereinafter, for instance, inhibits the growth of Chlorella vulgaris.

Preparation of the subject compounds proceeds simply by contacting a steroid of the formula OHZOH with a chlorosilane of the formula ClSiR in pyridine solution, R, R, R", R, X, X, Z, and the dotted lines in ring A having the meanings previously assigned. Addition to the reaction mixture of the corresponding hexaalkyldisilazane.

R SiNHSiR tends to enhance the yield.

The following examples describe in detail compounds illustrative of the present invention and methods which have been devised for the preparation thereof. However, the invention is not to be construed as limited thereby, either in spirit or in scope, since it will be apparent to those skilled in the art of organic synthesis that many modifications, both of materials and of methods, may be practiced without departing from the purpose and intent of this disclosure. Throughout the examples hereinafter set forth, temperatures are given in degrees centigrade and relative amounts of materials in parts by weight, except as otherwise noted.

EXAMPLE 1 21-trimethylsiloxy-5a-pregnane-3,20-dione To a solution of 20 parts of 2l-hydroxy-5u-pregnane- 3,20-dione in 500 parts of pyridine is added 34 parts of 3 trimethylchlorosilane and 77 parts of hexamethyldisilazane. The resultant mixture is stirred for 1 minute at room temperature, then allowed to stand thereat for 5 minutes. The mixture thus obtained is poured into 5000 parts of ice water. The waxy precipitate which forms is isolated by filtration, washed with water, dried in air, and recrystallized from hexane to give 21-trimethylsiloxy-5apregnane-3,20-dione melting 'at approximately 104405. The product has the formula CHzO Si(CH3)3 EXAMPLE 2 2l-trimethylsiloxy-55-pregnane-3,20-dione EXAMPLE 3 17a-hydroxy-2l-trimethylsiloxypregn-4-ene-3,11,20- trione To a solution of 4 parts of cortisone in 200 parts of pyridine is added 34 parts of trimethylchlorosilane and 62 parts of hexamethyldisilazane. The resultant mixture is stirred for 1 minute at room temperature, then allowed to stand thereat for 5 minutes. The mixture thus obtained is poured into 2000 parts of ice water. The oil which separates is removed and diluted with 264 parts of hexane, whereupon precipitation occurs. The precipitate is filtered olf after 2 hours at 5", dried in air, and recrystallized from ethyl acetate to give 17u-hydroxy-2l-trimethylsiloxypregn-4-ene-3,l1,20-trione melting at 187-189". The'product has the formula (EH2OSKOHQ3 4 EXAMPLE 4 9u-fluoro-11,3,17a-dihydr0xy-2l-trimethylsiloxypregn- 4-ene-3,20-dione To a solution of 2 parts of 9u-fiuoro-1lfl,l7a,2l-trihydroxypregnl-ene-B,20-dione in parts of pyridine is added 17 parts of trimethylchlorosilane and 31 parts of hexamethyldisilazane. The resultant mixture is stirred for 1 minute at room temperature, then allowed to stand thereat for 30 minutes. The mixture thus obtained is poured into 1200 parts of ice water. The oil which separates is extracted with ether; and the ether extract is Washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residual liquid solidifies on standing. Recrystallized from a mixture of ethyl acetate and hexane, it atfords 9a-fiuoro- 1 1,8,17a-dihydroxy-21-trimethylsiloxypregn-4-ene 3,20- dione which melts at 148, resolidifies above this temperature, and melts again at The product has the formula EXAMPLE 5 17a-acetoxy-9a-fluoro-1 1,3-hydroxy-21-trimethylsiloxypregna- 1 ,4-diene-3,20-dione To a solution of 2 parts of 17a-acetoxy-9a-fluoro-1118, 21-dihydroxypregna-1,4-diene-3,20-di0ne in 100 parts of pyridine is added 17 parts of trimethylchlorosilane and 29 parts of hexamethyldisilazane. The resultant mixture is stirred for 1 minute at room temperature, then held thereat for 5 minutes, and finally poured into 500 parts of ice water. The mixture thus obtained is extracted with ether. The ether extract is washed with water, dried over anhydrous sodium sulfate, and stripped of solvent by vacuum distillation. The residue is 17u-acetoxy-9a-fluoro- 11/8-hydroxy-2l-trimethylsiloxypregna-1,4-diene-3,20 dione, having the formula CHzOSKCHQ;

EXAMPLE 6 9a-fiuoro-l1B,l7a.-dihydroxy-16a-methyl-21-trimethylsiloxypregna-l ,4-diene-3,20-dione To a solution of 2 parts of 9a-fluoro-11fi,l7a, 21 trihydroxy 16cc methylpregna 1,4 diene 3,20- dione in 100 parts of pyridine is added 17 parts of trimethylchlorosilane and 29 parts of hexamethyldisilazane. The resultant mixture is stirred for 1 minute at room temperature, then allowed to stand thereat for 5 minutes. The mixture thus obtained is poured into 1200 parts of ice water. The oil which separates congeals to a waxy solid. The solid is filtered off, Washed with Water, dried in air, and crystallized from ethyl acetate to give 90:- filoro 115,170; dihydroxy 16a methyl-Zl-trimethylsiloxypregna-1,4-diene-3,20-dione, melting at 229232. The product has the formula CHzOSi(CH3)3 EXAMPLE 7 To a solution of 2 parts of 6a,9u-difiuoro-l1,8,16a,17a, 2l-tetrahydroxypregna-l,4-diene-3,20-dione cyclic 16,17- acetal with acetone in 100 parts of pyridine is added 17 parts of trimethylchlorosilane and 29 parts of hexamethyldisilazane. The resultant mixture is stirred for 1 minute at room temperature, then allowed to stand thereat for minutes. The mixture thus obtained is poured into 1000 parts of ice water. The oil which separates is extracted with ether. The ether extract is Washed consecutively with water and saturated aqueous sodium chloride, dried over anhydrous sodium sulfate, and stripped of solvent by distillation. The residue, recrystallized from ethyl acetate, affords 604,911 difluoro 11B,l60(,170c trihydroxy-Zl-trimethylsiloxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone melting at 234-240. The product has the formula CHzOSi(GH What is claimed is: 1. A compound selected from the group consisting of compounds of the formula and compounds of the formula CHzOSiR;

wherein R represents lower alkyl; R represents hydrogen, hydroxyl, or lower alkanoyloxy; R" represents hydrogen or methyl; X represents hydrogen or fluorine; Z represents methylene, fi-hydroxymethylene, or carbonyl; and the dotted lines in ring A indicate that the ring can be saturated, A or A.

2. A compound according to claim 1, the formula of which is C 03 O Si (lower alkyl) H3O OH 3. A compound according to claim 1 which is 2l-trimethylsiloxy-Sa-pregnane-3,ZO-dione.

4. A compound according to claim 1 which is 2l-trimethylsiloxy-5fi-pregnane-3,ZO-dione.

5. A compound according to claim 1 which is l7a-hydroxy-Z1-trimethylsiloxypregn-4-ene-3, 1 1,20-trione.

6. A compound according to claim 1 which is 9u-fluoro- 1lB,17ot-dihydroxy-2l-trirnethylsiloxypregn 4 ene3,20- dione.

7. A compound according to claim 1 which is 9m-filoro- 1113,17a dihydroxy 16a methyl 21 trirnethylsiloxypregna-l,4-diene-3,20-dione.

8. 60,9rx difluoro l1/3,l6a,l7tx trihydroxy 21 trimethylsiloxypregna-1,4-diene-3,20-dione cyclic 16,17-acetal with acetone.

References Cited UNITED STATES PATENTS 3,311,644 3/1967 Brown et al.

HENRY A. FRENCH, Primary Examiner US. Cl. X.R.

Page 1 of 2 UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Dated October 8, 1970 It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 5, "DIONES should be -DIONES AND CONGENERS- Column 1, line 23, "2l-tri(low alkyl)-' should be --2l-tri(lower alkyl)- Column 1, line 57, "R' should be -R Column 1, line 59, "acrylic" should be -acyclic-.

Column 2, formula H ll should be Column line 66, "trihydroxy 16a" should be trihydroxy-l6or.--.

Column line 75, "flloro" should be -fluoro--.

Column 5, first formula,

CH 035. (EH OS1(CH 3 11 5 c 00 H C CO should be Page 2 of 2? UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3, 515, 163 Dated October 8, 1970 Inventor(s) Edward A Brown It is certified that error a and that said Letters Patent are ppears in the above-identified patent: hereby corrected as shown below:

Column 5, third formula,

H I H C should be -ct O 0 Column 6, first formula should be :Ei I

F Column 6, second formula CH 0Si(lower alkyl) CO- OSi(lower alkyl) 2 H c j H 0 00 n 3 OH II should be Column 6, line 4 9on-flloro" should be --9OL- fluoro Signed and sealed this 15th day of December 1970 @EAL) Arms:

li'inmd M ."Iomher,h

WIEIEIAM E. 'SGEUYLHR. E. .atzeatimg 025cm- Gomissioner of Patents 

